What is Prostate Cancer (Neuroendocrine Carcinoma of the Prostate)?

The prostate is a gland found only in men. It surrounds the urethra (the tube through the penis that drains urine from the bladder), and sits at the base of the bladder. It is normally about the size of a walnut. The function of the prostate is to produce fluid that forms a component of semen. The prostate is made up of mainly glandular tissue; however, there are also some specialised epithelial (lining) cells called neuroendocrine cells. These cells secrete hormones, which act as chemical messengers in the body.

Cancer occurs when an abnormality occurs in the genes of a cell, causing it to multiply and interfere with the normal function of a tissue. Once the cancer reaches a certain size, the abnormal cells can spread to other parts of the body and causes cancerous tumours to grow there (this is known as metastasis). If a tumour is capable of spreading to other parts of the body in this way, it is called malignant.
If cancer arises in the neuroendocrine cells of the prostate, it is known as neuroendocrine carcinoma of the prostate. This is a rare form of prostate cancer.

Statistics

Prostate cancer is the sixth most common cancer in the world and the most common form of cancer in Australian men (apart from melanomas). Australia also has the highest incidence of prostate cancer in the world (105 cases per 100,000 males).
The mean age at diagnosis is 68.4 years old and 85% of new cases occur in men over 60.In men of all ages, 85% will live for 5 years or longer from the time of diagnosis.To age 85, a quarter of Australian men will be diagnosed with prostate cancer and 1 in 25 will die from it, making it the second leading cause of cancer death in Australia.
Although prostate cancer is the second most common cause of cancer in Aboriginal Australian males (after lung cancer), the rates are lower in Indigenous men than in non-Indigenous men. However, it is not clear whether Indigenous Australians are truly less likely to develop prostate cancer, or whether lower rates of screening and diagnostic testing as well as a shorter life expectancy are contributing factors. There has been a significant increase in the rates of diagnosed prostate cancer since the screening of asymptomatic men became popular in the 1990s.Primary neuroendocrine carcinoma is very rare and accounts for less than 5% of prostate cancers. More frequently, small sections of neuroendocrine carcinoma occur within the far more common adenocarcinoma form. This occurs because cancer cells are rapidly changing and dividing and tend to change their form.

Risk Factors

The predisposing factors that result in the neuroendocrine variant of prostate cancer remain unclear. The following risk factors relate to prostate cancer in general.Age
The main risk factor for prostate cancer is age.Prostate cancer is rarely diagnosed before the age of 40, then the incidence rises rapidly.PSA testing is not generally carried out on men aged under 50 unless they have significant risk factors. The rates of prostate cancer at different ages are as follows:

20 to 30 years: 2–8%;

31 to 40 years: 9–31%;

41 to 50 years: 3–43%;

51 to 60 years: 5–46%;

61 to 70 years: 14–70%;

71 to 80 years: 31–83%; and

81 to 90 years: 40–73%.

Genetics
Around 5–10% of prostate cancer is due to genetic defects, so men who have a family history are more at risk of developing it themselves. Men who have a first-degree relative (brother, father or son) who has had prostate cancer have a 2–3 times greater chance of developing prostate cancer themselves.This risk may be higher if the relative was diagnosed before the age of 60.
Identifying particular genes involved in prostate cancer has proved challenging. BRCA1 and BRCA2 genes are involved in a 2–5 fold increased risk of prostate cancer.
In American studies, African-American men have higher rates of developing prostate cancer than Caucasian or Hispanic men. Indigenous Australians are at a lower risk of being diagnosed with prostate cancer than non-Indigenous Australians.Diet
The links between prostate cancer and diet has been extensively studied. Significant findings include:

Diet high in animal fat may contribute to prostate cancer

A diet low in vegetables may be a risk factor for prostate cancer

Soy intake may have a modest protective effect against prostate cancer.

Other factors

Other men who are at increased risk of prostate cancer are those who have had elevated PSA tests, or abnormal prostate biopsies in the past.

Testosterone levels were previously thought to be related to development of prostate cancer; however, this does not appear to be the case.

Obesity may be linked with more aggressive forms of, but not increased incidence of prostate cancer.

Smoking has been linked to increased deaths due to prostate cancer in Caucasians.

Progression

In many cases, prostate cancer spreads so slowly that it never causes illness, and the patient will die of other causes. However, if the cancer is left untreated, it is possible that it will invade locally, spread to local pelvic lymph nodes, and eventually spread to other parts of the body (metastasise). This may eventually result in organ failure and death. Bony metastases from prostate cancer are common.
For men who choose not to undergo definitive local treatment, survival relates to the aggressiveness (histological grade) of prostate cancer.
In general, neuroendocrine carcinoma of the prostate is more aggressive and has a worse prognosis than conventional adenocarcinoma of the prostate.

Symptoms

Currently, most prostate cancer diagnosed is asymptomatic. The cancer is detected due to abnormalities in PSA levels.
In the past, prostate cancer was diagnosed due to abnormal digital rectal examination (DRE), or due to the presence of urinary symptoms such as difficulty starting urine stream, urgent rush to get to the toilet, needing to pass urine frequently at night, and dribbling of urine at the end of the stream. However, these urinary symptoms are more commonly caused by benign prostatic hyperplasia or bladder infections.
Other symptoms that may raise suspicion of prostate disease include new onset erectile dysfunction, blood in the urine, blood in the semen, or symptoms of metastasis such as bone pain.

Clinical Examination

The doctor will perform a digital rectal examination (DRE), where a gloved finger is inserted into the rectum (back passage) to feel the prostate, to determine if it is enlarged or if any lumps are present.
PSA and DRE are generally performed together to check for prostate cancer. PSA testing requires a blood test to be taken.

How is it Diagnosed

A blood test is carried out to check the levels of prostate specific antigen (PSA). If a man’s PSA level is elevated above 4 ng/mL, it may indicate that he is at increased risk of prostate cancer. However, most men with elevated PSA do not have prostate cancer. It must be noted that neuroendocrine carcinoma may not be detected as accurately by PSA as adenocarcinoma of the prostate, because some forms do not secrete PSA.

If further investigation is required, the next stage is usually a prostate biopsy, which is performed using ultrasound, via the rectum. An implement passes needles into the prostate, which are withdrawn with tissue inside them. The prostate tissue is examined under a microscope to determine if cancer is present, what type it is, and how aggressive it is. Serious complications due to prostate biopsy are rare. Hospitalisation (usually for urinary infections), or urinary retention occur in less than 1% of cases.One study found the following side-effects for biopsy: blood in the semen (51%), blood in the urine (23% longer than three days), fever (3.5%) and rectal bleeding (1.3%). These symptoms were generally short term.
If cancer is identified on biopsy, the doctor will then carry out further investigations, such as removal of local lymph nodes, or CT, to determine whether the cancer has spread.

Prognosis

The risk of a man being diagnosed with any type of prostate cancer at some point in his life is 1 in 6 (17%). However, only 3% of men die from prostate cancer. At autopsy, one third of men under the age of 80 and two thirds of men over the age of 80 are found to have some form of prostate cancer.This data suggests that most men die with prostate cancer, rather than from it. At five years, 99% of men diagnosed with prostate cancer are still alive. At 10 years, 95% of men diagnosed with prostate cancer are still alive.
Determining the degree of spread of the cancer is known as ‘staging’. Cancer that is confined to the prostate gland is generally curable. Prognosis is less good if the cancer has spread locally. If the cancer has spread to other parts of the body such as the bones, it is very difficult to cure. Treatment is focused on slowing the spread of the disease, and men may still live for many years with a good quality of life. Prognosis is also related to the grade of the cancer, which in general is higher in neuroendocrine than in adenocarcinoma of the prostate. This means that neuroendocrine cancer is a more aggressive variety, so the prognosis is worse. Because it is rare, more specific figures related to prognosis are unavailable at this stage.

Treatment

Treatment options for prostate cancer include:

Active surveillance;

Radical prostatectomy;

External beam radiotherapy;

Brachytherapy (internal radiotherapy); and

Hormonal therapy.

Active surveillance
The risk of some small, non aggressive, localised prostate cancers ever spreading is very low. In this case the risks of treatment may outweigh the benefits. A doctor may therefore recommend ‘watchful waiting’, also known as ‘active surveillance’. The cancer and PSA levels are monitored, but no active treatment is carried out. This may be particularly appropriate for men who have a life expectancy of less than 10 or 15 years due to advanced age or other medical problems.
Treatment in Australia
If a man chooses to have treatment for the prostate cancer, the main options in Australia include surgery, radiotherapy and hormone therapy. There is no good quality evidence that one approach is superior to the others, so treatment choice is based on the following considerations:

Age, general medical condition and other medical problems. If a man has a less than 10 year life expectancy, definitive treatment may not be recommended.

Serum PSA and Gleason Score. The Gleason Score is determined following prostate biopsy and is a measure of the aggressiveness of the cancer. If these levels are high, it may indicate the cancer is more aggressive, so more aggressive treatment may be justified.

Spread of the prostate cancer. If the cancer has already spread to bones and other organs, treatment aiming to cure the disease is not likely to be effective. Treatment options such as palliative radiotherapy may then be used to treat pain and other symptoms.

Outcomes associated with treatment options. Various treatments may have different outcomes, and need to be considered in the context of the individual patient, and the specifics (location, aggressiveness etc) of their disease. There is not a single treatment that results in the best outcome for all patients with prostate cancer.

Side effects and quality of life implications related to treatment options. Each of the treatment options has different side effects. Each patient needs to evaluate how he feels about the possibility of such side effects (such as sexual dysfunction), and weigh up the risks and benefits of each procedure to determine which is most appropriate for him.

Radical prostatectomyRadical prostatectomy (RP) involves removal of the prostate via a lower abdominal incision, or via keyhole surgery (laparoscopic). RP generally involves a 4-8 day hospital stay. A urinary catheter (tube through the penis into the bladder) with a urine bag attached remains in place for at least 2 weeks post operatively. Death rates due to radical prostatectomy are 0.5%, increasing to 1% in men over 75 years. Sexual dysfunction may occur in 20-70% of patients, and urinary problems in 15-50% of patients following radical prostatectomy.Bilateral nerve sparing surgery may be possible in some cases, with reduced side effects. In some cases, RP may be followed by radiotherapy.Radiotherapy (external beam radiation therapy)External beam radiation therapy (EBRT) may be used with RP or hormonal therapy to treat prostate cancer. Beams of radiotherapy (like x-rays) are targeted at the prostate by a machine that moves around the body. The rays kill the cancer cells. Small tattoos may be placed on the skin to make sure the beam is in exactly the right place, and minimise healthy tissue being damaged. This procedure is performed in an outpatient setting, and men are usually able to maintain their normal activities. Radiotherapy may lead to sexual dysfunction in 20-45% of cases, urinary incontinence in 2-16%, and bowel dysfunction in 6-25% of men who were previously normal in these areas.Brachytherapy (internal radiotherapy)
There are two main types of brachytherapy. One involves the insertion of a radioactive pellet into the prostate (seeding). The pellet loses its radioactivity over time, and is not removed. This option may be used for low Gleason score, low PSA, small localised prostate cancer. Side effects such as painful urination, poor urine flow and bladder irritation are common. These can start a month after treatment and gradually get better over 12 months. The second type of brachytherapy involves insertion of wide bore needles into the prostate, through which radioactive sources can be administered. After several days of treatment, the needles are removed. This type of brachytherapy is used in conjunction with EBRT, for larger more aggressive tumours. The needles may cause local discomfort, usually relieved by painkillers. Other side effects are similar to those for EBRT.Hormonal therapy (androgen deprivation therapy)Hormone therapy may be used in addition to EBRT. It is also commonly used for prostate cancer that cannot be cured (palliative treatment). It has not been shown to improve outcomes when used before treatment with surgery. Testosterone appears to drive the growth of prostate cancer. Androgen Deprivation Therapy (ADT) aims to lower levels of testosterone. This may be achieved through removal of the testes (often replaced with prosthetic testes) or medical castration with drugs. These include buserelin or goserelin, and cyproterone acetate or flutamide).
Side effects of ADT include hot flushes, loss of libido (sex drive), weight gain, erectile dysfunction (impotence), gynecomastia (swelling of the breasts), fluid retention, softening of the bones (osteoporosis) and mood swings.Palliative treatments
In some cases, when prostate cancer is diagnosed, it is too advanced to be cured by surgery or radiotherapy. In these cases, treatment is referred to as ‘palliative’. Palliative treatment is designed to relieve symptoms, maintain quality of life, and in many cases, prolong life but it will not cure the disease.

Transuretheral Resection of the Prostate (TURP) may be carried out to relieve obstructive symptoms due to the cancer.

Hormone therapy- ADT is a mainstay of treatment for cancer that is not resectable. Eventually, the cancer will no longer respond to ADT. At this point as prognosis is poor, with an average survival of 1 year once symptoms occur.

Bisphosphonates and analgesia may be used to treat bone metastases

EBRT may be used to treat pain related to bone metastases, and improves pain in 80-90% of cases with complete pain response in 50-60% of cases.

Relative side effects of different treatments

Radical prostatectomy and brachytherapy result in higher rates of urinary incontinence and sexual dysfunction than EBRT. Bilateral nerve sparing surgery (not possible in all cases) diminishes this difference.

Roder D. Epidemiology of cancer in Indigenous Australians: Implications for service delivery. Paper presented at the 9th National Rural Health Conference: Standing up for rural health: Learning from the past, action in the future. Albury, NSW: 7-10 March 2007. Available from: URL link